The proposed research focuses on the neuropeptide glucagon-like peptide-1 (GLP-1) and its role in controlling for food intake and body weight through action in the central nervous system (CNS). FDA-approved GLP-1 receptor (GLP-1R) agonists for the treatment of Type II Diabetes Mellitus (T2DM) produce improvements in blood glucose regulation and, in addition, produce meaningful reductions in food intake and body weight in both humans and animal models. Therefore, recent attention has been given to long-acting GLP-1R agonists as a potential treatment for obesity. The importance of GLP-1 signaling on vagal afferents and in hindbrain and hypothalamic nuclei [e.g. nucleus tractus solitarius (NTS) and paraventricular hypothalamus] is established for the homeostatic or need-based control of food intake. However, given that the excessive food intake that contributes to human obesity is not driven by metabolic need alone, it is critical to examine and better define the neural basis of non-homeostatic controls of food intake. As GLP-1R are also expressed in brain regions associated with reward and cognitive processes, determining the mechanism by which GLP-1 signaling contributes to the non-homeostatic control of feeding is a priority and focus of this application. It is also very clear that more progress could be made in the treatment of obesity if research identifies specific CNS nuclei and mechanism(s) mediating GLP-1's effects on energy balance, as well as investigate whether other neurochemical systems that also contribute to energy balance interact with and enhance CNS GLP-1R-mediated intake inhibitory effects. Experiments in this proposal will utilize novel approaches that combine neuropharmacological, behavioral, molecular, genetic, immunohistochemical, electrophysiological, and advanced surgical techniques to examine: [1] whether vagal satiation signals from the gastrointestinal tract inhibit food intake in part via mediation by NTS GLP-1 projections to the nuclei of the mesolimbic reward system [e.g. ventral tegmental area (VTA) and nucleus accumbens (NAc)]; [2] whether dopaminergic and glutamatergic mechanisms mediate the intake suppressive effects of GLP-1R signaling in the VTA and NAc; [3] NTS GLP-1R-mediated transcription and protein synthesis changes that integrate with and potentiate intake and body weight suppressive effects of other NTS-modulated anorectic systems. The overall research proposed will provide a framework for development of more effective GLP-1R-mediated treatments for obese individuals. In addition, results may help identify potential targets for combination drug therapy to enhance the food intake and body weight suppressive effects of GLP-1- based pharmaceuticals.